Neuroprotective Strategy: Novel Purine Derivatives for Neonatal Hypoxia-ischemia

神经保护策略：治疗新生儿缺氧缺血的新型嘌呤衍生物

• 批准号: 10219376
• 负责人: BARBARA S STONESTREET
• 金额: $ 51.53万
• 依托单位: WOMEN AND INFANTS HOSPITAL-RHODE ISLAND
• 依托单位国家: 美国
• 财政年份: 2021
• 资助国家: 美国
• 起止时间: 2021-05-01 至 2026-01-31
• 项目状态: 未结题
• 来源: https://reporter.nih.gov/project-details/10219376
• 关键词: 2 year old; Adult; Aging; Anatomy; Anti-Inflammatory Agents; Apoptosis; Attenuated; Behavioral; Biological Assay; Biological Markers; Birth; Blood - brain barrier anatomy; Blood Vessels; Brain; Brain Hypoxia-Ischemia; Brain Injuries; Cell Death; Cerebrovascular system; Cessation of life; Cognition; Cognitive deficits; Complement; Data; Deterioration; Dose; Encephalopathies; Erythropoietin; Exposure to; Extravasation; FDA approved; Family; Female; Functional disorder; Genetic Transcription; Human; Impairment; In Vitro; Infant; Infarction; Inflammation; Inflammatory; Inflammatory Response; Injury; Legal patent; Life; Magnetic Resonance Imaging; Measurement; Mitochondria; Modeling; Morbidity - disease rate; Motor; Mus; Neonatal; Neurodevelopmental Disability; Neurodevelopmental Impairment; Neuronal Plasticity; Neurons; Newborn Infant; OPA1 gene; Optics; Pathway interactions; Pharmaceutical Preparations; Pharmacological Treatment; Pharmacology; Premature Infant; Property; Proteins; Protocols documentation; Publishing; Purines; Rattus; Reflex action; Rice; Risk; Rodent; Short-Term Memory; Signal Pathway; Structure; Supportive care; Testing; Therapeutic; Therapeutic Agents; Vascular Endothelium; behavioral outcome; blood-brain barrier disruption; blood-brain barrier function; brain cell; brain metabolism; experience; experimental study; glycogen synthase kinase 3 beta; improved; in vivo; innovation; ischemic injury; male; morris water maze; natural hypothermia; neonatal hypoxic-ischemic brain injury; neonate; neurobehavioral; neurogenesis; neuroimaging; neuroinflammation; neuroprotection; neurotrophic factor; neurovascular; neurovascular unit; new therapeutic target; novel; novel strategies; open field behavior; prevent; prohibitin; protective effect; respiratory; response; standard of care; synaptic function; treatment strategy; vascular bed; way finding

PROJECT SUMMARY/ABSTRACT Hypoxia-ischemia (HI) is the one of leading causes of neurodevelopmental morbidities in preterm and full-term infants. The only therapeutic strategy to treat HI encephalopathy (HIE) in full term infants is hypothermia, which is only partially protective. The only therapy for HI in preterm infants is supportive care. HI brain injury is characterized by a pronounced inflammatory response along with early structural alterations in the blood-brain barrier (BBB)/neurovasculature unit (NVU). Both inflammation and BBB abnormalities predispose to neuronal damage. In the current proposal, we investigate a novel family of molecules, which are purine derivatives (PDD), acting through GSK-3β and prohibitin (PHB) pathways. PHB protects the integrity of OPA1 in brain mitochondria, which is a particularly important protective protein in the immature brain. Previous studies have shown that OPA1 prevents mitochondrial permeabilization, respiratory deterioration and apoptosis in neurons and vascular beds. Our published data show that PDD i) rescue cognitive deficits associated with aging in mice, ii) prevent impairment of neurogenesis, iii) enhance synaptic function and iv) reduce neuroinflammatory brain injury in adult mice. GSK-3β and PHB signaling pathways, including NF-kβ, are involved in the neuroprotective mechanisms of PDD. Our preliminary results in the well-characterized Rice-Vannucci model of neonatal HI showed that PDD given after HI i) decreased in the HI related infarct volumes by 40%. Our preliminary data suggests PDDs exert i) important and consistent neuroprotective effects in neonatal and adult models of brain injury, ii) increased OPA-1 expression and iii) increased the transcriptional expression of neurotrophic factors in treated female, but not male, neonatal rats after HI. These results suggest induction of neuronal plasticity and OPA-1 expression in this model that could be beneficial after neonatal HI. The overall hypothesis of our proposal is that PDD targets GSK-3β and PHB to attenuate both the BBB abnormalities and inflammation after neonatal HI. We will test this major hypothesis in two specific aims: Aim 1: PDD303 attenuates brain injury in neonatal rats after exposure to moderate and severe HI. Aim 2: Treatment with PDD303 improves behavioral outcomes and demonstrates durable long-term neuroprotective efficacy after HI in neonatal subjects. We anticipate that this innovative therapeutic strategy targeting the BBB and neuroinflammation through GSK3β and PHB could eventually provide an additional treatment strategy to the current standard of care for both full term and premature infants.

项目总结/摘要 缺氧缺血（Hypoxia-ischemia，HI）是早产儿神经发育疾病的主要原因之一， 足月婴儿治疗足月婴儿HI脑病（HIE）的唯一治疗策略是 体温过低，这只是部分保护。早产儿HI的唯一治疗方法是支持疗法 在乎HI脑损伤的特征在于明显的炎症反应沿着早期的炎症反应。 血脑屏障（BBB）/神经血管单位（NVU）的结构改变。两种炎症 和BBB异常易导致神经元损伤。在当前的提案中，我们调查了一部小说 嘌呤衍生物（PDD）分子家族，通过GSK-3β和抑制素（PHB）发挥作用 途径。PHB保护脑线粒体中OPA 1的完整性，这是一个特别重要的作用。 未成熟大脑中的保护蛋白以前的研究表明，OPA 1可以预防 神经元和血管床中的线粒体透化、呼吸恶化和细胞凋亡。 我们发表的数据表明，PDD i）挽救与小鼠衰老相关的认知缺陷，ii）预防 损伤神经发生，iii）增强突触功能和iv）减少神经炎性脑 成年小鼠的损伤。GSK-3β和包括NF-kβ在内的PHB信号通路参与了 PDD的神经保护机制我们在良好表征的Rice-Vannucci中的初步结果 新生儿HI模型显示，HI后给予PDD i）通过降低HI相关梗死体积， 百分之四十我们的初步数据表明PDDs发挥i）重要和一致的神经保护作用， 新生儿和成人脑损伤模型，ii）OPA-1表达增加和iii）OPA-1表达增加。 在HI后处理的雌性而非雄性新生大鼠中神经营养因子的转录表达。 这些结果表明，在该模型中诱导神经元可塑性和OPA-1表达， 对新生儿HI有好处。我们建议的总体假设是PDD靶向GSK-3β， PHB可减轻新生儿HI后的BBB异常和炎症。我们将测试这个 两个具体目的的主要假设：目的1：PDD 303减轻新生大鼠脑损伤， 暴露于中度和重度HI。目的2：PDD 303治疗改善行为结果 并且在新生受试者中HI后显示出持久的长期神经保护功效。我们 预计这种创新的治疗策略通过以下方式靶向BBB和神经炎症： GSK 3 β和PHB最终可以为目前的标准治疗提供额外的治疗策略。 照顾足月和早产儿。